Blog

Contract Manufacturing (CMO) Management

Pharmaceutical contract manufacturing refers to the practice of contracting out the production of pharmaceuticals, such as pills, tablets, and capsules, for a third party to consume.

Contract Manufacturing (CMO) Management

  • Purpose

    • The purpose of this standard operating procedure is to describe the procedure for Management of Contract Manufacturing service provided by contract Manufacturing Company, which includes identification, assessment, approval, technical agreement and approval of Contract manufacturing company (CMO) and their periodic assessment.
    • To ensure that the Contract Manufacturer deliver reliably and consistently Manufacturing of product, GMP related activities, in accordance with cGMP / GDP/GLP quality requirements and applicable regulatory requirements.
    • To define the rules for risk based quality management of Contract manufacturing activity by establishing the requirements for selection, assessment, qualification and monitoring.

  • Scope

    • This Standard Operating Procedure is applicable to all Contract Manufacturing services under “cGMP” purview for manufacturing and Testing of drug product.
    • This SOP is applicable to all types of formulations.

  • Responsibility

    • Third Party Coordinator shall be responsible for;

      • Conduct market search for potential manufacturer for required product.
      • Contribute to collection of manufacturer information and its maintenance.
      • Arrange filled questionnaire from contract manufacturer.
      • Support Quality department to select and qualify a new manufacturer.
      • Participate in Audit along with audit team
      • Assure, establishment and approval of supply agreement.

    • Contract Manufacturer shall be responsible for;

      • Provide Filled Questionnaire to contract giver (CG) along with all supporting documents.
      • Manufacture and packed product as per the approved MFR/BMR/BPR and agreed specification.
      • Inform contract giver (CG) when an OOS/OOT results is obtained/identified.

    • Contract Giver – Quality Control/Quality Assurance shall be responsible to;

      • Participate in Audit along with audit team.
      • Review Filled Vendor questionnaire and other documents i.e. SMF, Manufacturing Licence, WHO-GMP Certificate etc., received from Contract Manufacturer.
      • Coordinate with third Party coordinator for Resolving query if any.
      • Prepare facility audit report and send to Contract Manufacturing Company through Third Party Coordinator.
      • Review the audit compliance report
      • To maintain a consolidated list of Contract Manufacturing Company.

  • Procedure for management for management of contract manufacturing (CMO)

    • Identification and preliminary assessment of Contract Manufacturing Company:

    • Identification:
    • Whenever need for manufacturing of drug product at outside required, Third party coordinator shall conduct market search for potential manufacturer for required product(s).
    • Identification of new contact manufacturing facility shall be based on drug product requirement. Head third party shall identify the scope of Contract manufacturing for required drug product.
    • Once Contract manufacturing facility identified, Head third party shall communicate to Head Quality along with the list of product (s) which will be manufactured at Contract manufacturing, for necessary assessment and approval.
    • Selection, Assessment and approval of Contract manufacturing facility shall be done based on the nature of product and contract givers (CGs) cGMP/GLP/GDP requirement.

    • Following criteria may be considered during identification of Contract manufacturing facility.

    • Evaluate the need for the manufacturing facility to be GMP/GLP compliant or not.
    • Experience with product development and/or process validation, cleaning validation and method validation/verification according to GMP/GLP requirements.
    • Experience with preparation of Specifications, QC activities and approval of QC results according to GMP requirements.
    • Manufacturing Facility Accreditation.
    • Accreditation of former inspection history.
    • Availability of equipment/capacity for manufacturing and testing of drug product.
    • Availability of technical knowledge and expertise.
    • Adequacy, availability and suitability of laboratory equipment and resources.
    • Cost competitively.
    • Innovative and technical competencies.
    • Responsiveness and communication.
    • Sampling handling, transport and frequency.

    • Preliminary Assessment;

    • Quality department shall initiate the assessment of identified Contract Manufacturing facility based on drug product manufacturing requirement by arranging the questionnaire through Third part coordinator.
    • Quality department shall ask contract manufacturing facility to provide filled questionnaire along with SMF, List of manufacturing equipment, list of Quality control Instruments, Utility equipment, HVAC details, water system details, List of technical person in Production and QC, list of Accreditation etc.
    • Filled Questionnaire, SMF and all supporting documents received from Contract manufacturing facility shall be reviewed by QA and approved by Head Quality if found satisfactory.
    • If the preliminary assessment based on details provided through questionnaire is satisfactory, the Contract Manufacturing facility shall be shortlisted for the required product manufacturing services and proceeded for next step of assessment.

    • Audit of Contract manufacturing facility:

    • Shortlisted Contract manufacturing facility shall be audited as per procedure described in these sections.
    • Quality department shall arrange these audits in co-ordination with Planning Department and where available shall lead the Audit.
    • Head Quality department /Designee shall form audit team and shall make sure that audit is conducted by a qualified SMEs & auditor; Resources from QA, QC, Production or material and planning may be utilized.

    • Scope of Audit and Audit Procedure of Contract Manufacturing Facility

    • Audit approach is to find the objective evidences. Auditor is expected to cover Quality Management System, adequacy of facility, suitability of equipment/ instruments, competency of the personnel, status of validated procedure etc.
    • Objective of the audit is to confirm compliance of the site to relevant Good Manufacturing Practice and Good Distribution Practices. The following guidelines shall be considered during facility audit.
    • Audits should be of an appropriate duration and adequate man hours to be employed (based on scope and complexity of audit) and scope to ensure that a full and clear assessment of GMP is made; consideration should be given to potential cross- contamination from other materials on site.
    • It is recommended to audit all the process covered in the manufacturing of drug product.

    • The following could be some essential processes, but not limited to;

    • Starting Materials used, Qualification of supplier for starting material.
    • Receipt, verification, storage of materials.
    • Dispensing of materials for the manufacturing process.
    • Stages involved (i.e. For tablet/Capsule: Dispensed material storage, Granulation, Compression, Coating, packing. For Liquid: Bulk Manufacturing, Filtration of bulk, Bottle Filling & Packing etc.) in manufacturing of product. Key process parameters of each stage for the suitability and how process is controlled.
    • Specification/ Acceptance Criteria at each stage are met before proceeding to next stage.
    • Bulk packing of finished drug substance, Storage and dispatch etc.
    • Review of any activity that is subcontracted.
    • Refer and review regulatory audit reports for similar observations in data/process related to the product.

    • Cover all products under scope of audit.

    • In the beginning of the audit, Auditor(s) shall arrange Opening Meeting to share audit agenda, expectation of the audit and request for documents, if required in advance. Opening meeting may include the following, but not limited to;
      • Introduction/roles/attendance.
      • Objective/scope/criteria.
      • Audit progress.
      • Interim/Closing meetings.
      • Reporting methods including nonconformity.
    • During audit, issues related to regulatory findings shall be verified. Compliance to the observations by the vendor shall also be verified.
    • During audit, the audit team shall review the previous contract giver’s audit observations and their compliance, if applicable.
    • At the end of the audit, auditor(s) shall arrange Closing Meeting to share the observations.

    • The following shall be considered during closing meeting;

    • Hold the closing meeting to present audit findings.
    • Cover situations encountered during audit that may decrease reliance on audit conclusions.
    • Discuss and resolve diverging audit findings and conclusions.
    • Keep a record if not resolved.
    • Provide recommendations for improvement where specified by audit objectives.
    • Keep minutes and attendance records
    • Auditor may use the check list “Facility Audit Check list for Contract Manufacturing facility” as a guiding tool during the audit.
    • Auditor shall collate the information from users of the materials on the issues with vendor and/or materials received e.g. Rejections, OOS, Complaints pertaining to materials being used and if required these aspects shall be covered in audit. Also shall refer previous audit observations for verifying compliance
    • At the end of audit, auditor shall brief the observations to the auditee team and discuss, if any disagreement with the observations. If any critical observation is identified, request shall be made for early closure of CAPA.
    • Audit report shall be as detailed as possible that shall reflect what was done and seen in the audit with any discrepancy clearly identified.

    • Audit observations shall be classified as follows, Critical, Major and Minor based on their impact on Quality (but not limited to):

    • Critical: Any observation, which can affect the SISPQ of the product, which may pose serious health risk to the end user.
    • Major: Any observation from the validated and or established process, systems and practices which individually or if put together may affect SISPQ of the product, but does not affect health of the end user.
    • Minor: Any observation which is departure from standard operating procedure or specification or current good manufacturing practices (cGMP) violation, which will not affect SISPQ (Safety, Identity, Strength, Purity and Quality) of the product.
    • Contract Manufacturer shall be asked to send compliance plan along with supporting documents in about 30 days from the date of receipt of report.
    • In case of critical observation for existing contract manufacturer they shall be requested to send the compliance report within 15 days. On receipt of compliance report Auditor shall re-visit the site at the earliest date and check the execution and effectiveness of CAPA. contract giver shall not procure any material till site re-visited and CAPA execution checked by the Auditor. Quality department shall inform Third party coordinator Parallel for critical observation, if any.
    • Based on the Audit observation QA shall intimate to Third party coordinator about audit conclusion as per Annexure, “Audit Conclusion Intimation Form”.
    • After the receipt of compliance plan, it shall be reviewed by the auditors for adequacy and suitability and communicate to the vendor by Auditors through Planning Department and QA, if any deficiencies observed.

    • The approval status could be any of the following;

    • Approved: If the Contract Manufacturing Facility meet the cGMP/GLP/GDP requirements, no critical observations during audit and the compliance plan is acceptable for the other observations if any, than status shall be assigned by Head Quality/Designee as approved.
    • Rejected: In case, where there are noted observation of critical cGMP/GLP/GDP deficiencies in the Contract Manufacturing facility and quality systems, the Contract Manufacturing facility shall not be considered for the approval of Contract Manufacturing. If the Contract Manufacturing Facility is existing approved facility; manufacturing of product shall be suspended until a re-audit is done to assess cGMP status.
    • Upon satisfactory response and corrective/preventive actions by Contract manufacturer, contract giver shall issue an Audit Closure Report which shall conclude Approval/Rejection status of Contract Manufacturer and a copy of the same shall be shared with Quality department.

    • Technical Quality Agreement:

    • Technical Quality Agreement shall be in place between contract giver and approved Contract Manufacturer. Technical Quality Agreements shall be done.
    • QA shall initiate Quality Agreement with approved Contract Manufacturer through Third Party Coordinator. Terms and conditions may be discussed between contract giver and Contract Manufacturer and agreed prior to Technical Quality agreement, if vendor suggests different format it may also use upon mutual agreement.
    • In case of any changes in Manufacturing Process, Analytical Method or Regulatory issues, the vendor shall inform in writing to third party coordinator and same shall be intimated to Head Quality.
    • Technical Quality Agreements shall be uniquely identified as below given format number along with revision number and shall be tracked for revisions; XX/TA/YY/ZZZ-RR.
    • XX: stands for contract giver’s
    • TA: Stands for Technical Quality A
    • YY: Stands for type of Service i.e. LL for Loan Licenance, TP for third Party.
    • ZZZ: Stands for serial number starting from 001, 002,003… and so on.
    • RR: Stands for revision number. First revision shall be number as ‘00’ and 01, 02….and so on.

  • Periodic Audit (Re-Audit)      

    • Contract manufacturing facility shall be re-audited once in three years, unless any issue identified with contract giver on the Product/services provided by Contract manufacturing facility and/or regulatory issue.
    • List of approved Contract Manufacturing facility shall be maintained by QA. This list which also shows audits due for the year.
    • Need based/For Cause Audits: These audits are conducted as per request of Head QA, in the following cases, but not limited to;
    • To investigate market complaint received at contract giver product due to product supplied by contract manufacturer.
    • In case of serious regulatory findings, “For Cause Audit” shall be performed within 30 days from the date of receipt of audit observations.
    • Verification of compliance to CAPA proposed by vendor audit observations given by contract giver if required.
    • If vendor site has received warning letter by regulatory agencies. Audit shall be planned as part of risk mitigation activity, to verify impact on related data/product etc.

    • General Conditions:

    • QA shall provide support to provide batch numbering procedures, Batch Manufacturing record, Batch Packing record, Raw material/packing material specifications and Test procedure to contract manufacturer in case of Product to be manufacturer on LL basis.
    • Head Production and Head QC of contract giver shall depute technical person to contract manufacturing site for initial batches to be manufacture at contract manufacturing site for technical .
    • Any Non-conformance results (OOS/OOT) arising during the manufacturing of products shall be addressed to contract giver QA through Third party coordinator of
    • Any changes related to Specification, Standard Test Procedure shall be shared with Contract Manufacturer.
    • Contract Manufacturer shall submit each batch sample to contract giver as per requirement of contract giver for testing.
    • Contract giver shall perform Full/Partial testing on each batch and if sample does not comply with respect to specification, contract giver shall ask to Contract Manufacturer for investigation and CAPA. If required contract giver will assist to contract manufacturer for investigation.

    • Periodic Evaluation:

    • The Assessment of Contract manufacturer performance shall be performed once in year by contract giver’s team.
    • The following data should be evaluated and filled in Format by contract giver’s and shall be approved by Head QA/Designee.
    • Any discrepancy/observation identified.
    • Customer complaints received during review period.
    • Incident/Deviation/OOS/OOT reported by Contract Manufacturer reported during review period.
    • Adherence to agreed timelines and Adherence to Quality Agreement.
    • Audit results (own audits, authorities or third parties — if agreed upon).
    • Changes (methods, equipment and specifications).
    • Responses on audit and remediation plan/Response times for complaints and
    • Changes in certification/accreditation status.
    • During periodic evaluation of any adverse trends related to the test results shall be documented.
    • After the periodic evaluation Head QA/Designee shall decide on continuation of services.

  • Attachments 

Format – 01 : Contract Manufacturing Questionnaire
Format – 02 : Contract Testing Qualification Documents Tracking System
Format – 03 : List Of Approved Contract Manufacturing Facility
Format – 04 : Technical Agreement
Format – 05 : Periodic Evaluation of Contract Testing Laboratory
Format – 06 : Template for Audit Report
Annexure-I : Flow chart
  • REFERENCES
    • FDA Guidance for Industry – Contract Manufacturing Arrangements for Drugs: QualityAgreements.
    • PIC/S Guide to Good Manufacturing Practices for Medicinal Products PE 009-10: Part I, Chapter 7 (GMP clauses 7.1, 7.2, and 7,10 to 7.15).
    • APIC Guideline for Qualification & Management of Contract Quality Control , January-2012
    • WHO-TRS-986, Annexure-II

 

  • ABBREVIATIONS
API : Active Pharmaceuticals Ingredients.
CG : Contract Giver
CA : Contract Accepter
CTL : Contract Testing Laboratory
CAPA : Corrective Action and Preventive Action
DP : Drug Product
DCGI : Drug Controller General of India
DS : Drug Substance
cGMP : Current Good Manufacturing Practices
EU : Europium Union
CFR : Code of Federal Regulation
ICH : International Conference of Harmonization
NABL : National Accreditation Board for Testing and Calibration Laboratory
OOS : Out of Specification
OOT : Out of Trend
SME : Subject Matter Expert
QA : Quality Assurance
QC : Quality Control
SOP : Standard Operating Procedure

 

Tags: , , ,

pharmabeginers

Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

Leave a Reply